PROPELLANTSPROPELLANTS
BYBY
MADHU BURRA
(M PHARM II- SEM)(M PHARM II- SEM)
DEPARTMENT OF INDUSTRIAL PHARMACYDEPARTMENT OF ...
CONTENTSCONTENTS
 INTRODUCTIONINTRODUCTION
 CLASSIFICATIONCLASSIFICATION
– LIQUEFIED GASESLIQUEFIED GASES
– COMPRESSED G...
 Pharmaceutical aerosols are defined as “ products
containing therapeutically active ingredients
dissolved, suspended, or...
Components of an AerosolComponents of an Aerosol
 PropellantPropellant
 ContainerContainer
 Valve and actuatorValve and...
PROPELLANTS
 The propellant is generally regarded as theThe propellant is generally regarded as the
heart of the aerosol ...
CLASSIFICATIONCLASSIFICATION
 Liquefied gasesLiquefied gases
 Chlorofluorocarbons (CFC’s)Chlorofluorocarbons (CFC’s)
 H...
Liquefied - gasesLiquefied - gases
Liquefied gases have been widely used as
propellants for most aerosol products.
Since t...
CHLOROFLUOROCARBONSCHLOROFLUOROCARBONS
(CFC’S)(CFC’S)
 chlorofluorocarbons (CFC’s) are inert,
non toxic, non-inflammable ...
Conti….Conti….
 Several of the fluorinated hydrocarbons have an
expansion ratio of about 240 , that is 1 ml of
liquefied ...
NOMENCLATURENOMENCLATURE
 To refer easily to the Fluorinated
hydrocarbons a relatively simple system of
nomenclature was ...
Conti….Conti….
 The number of chlorine atoms (for CFC’S) in the
compound is found by subtracting the sum of the
fluorine ...
PHYSICAL PROPERTIESPHYSICAL PROPERTIES
 Solubility- Non polar
 Boiling point- below 240
C
 Density - >1
 Vapor pressure
VAPOR PRESSUREVAPOR PRESSURE
 It is defined as the pressure exerted by a
liquid in equilibrium with its vapor.
 It is de...
Conti…Conti…
 The vapor pressure of a mixture of propellants can
be calculated by using Raoult’s law.
Pa = [na/na+nb] PO
...
BLENDS OFBLENDS OF
CHLOROFLUOROCARBONCHLOROFLUOROCARBON
PROPELLANTSPROPELLANTS
PROPELLANT
BLEND
COMPOSITI
ON
VAPOR
PRESSUR...
PROPERTIES OFPROPERTIES OF
CHLOROFLUOROCARBONS (CFC’S)CHLOROFLUOROCARBONS (CFC’S)
PROPERTY TRICHLORO
MONOFLUOR
O METHANE
D...
CHEMICAL PROPERTIESCHEMICAL PROPERTIES
 HydrolysisHydrolysis
 Reaction with alcohol- All propellantsReaction with alcoho...
AdvantagesAdvantages
 Lack of inhalation toxicityLack of inhalation toxicity
 Lack of flammability andLack of flammabili...
DisadvantagesDisadvantages
 Destructive to atmospheric OzoneDestructive to atmospheric Ozone
 Contribute to “greenhouse ...
Destruction of OzoneDestruction of Ozone
 Ozone can be destroyed by a number of free radical
catalysts, the most importan...
Conti…Conti…
CFCl3 + hν → CFCl2 + Cl
Cl + O3 → ClO + O2
ClO + O → Cl + O2
In sum O3 + O → O2 + O2
=>Increase rate of recom...
Conti…Conti…
 It is calculated that a CFC molecule takesIt is calculated that a CFC molecule takes
an average of 15 years...
Ozone hole in September 2006Ozone hole in September 2006
“Largest hole in the record.
~Size of North America
September 16 ...
Consequences of Ozone depletionConsequences of Ozone depletion
 Since the ozone layer absorbs UVBSince the ozone layer ab...
HYDROCARBONSHYDROCARBONS
 These are used in topical pharmaceutical
aerosols.
 They are preferred for use as a propellant...
Conti…Conti…
 They can be blended with one another and
with the fluorocarbons to obtain the desired
vapor pressure and or...
FLAMMABILITY OF PROPELLANT 22FLAMMABILITY OF PROPELLANT 22
BLENDSBLENDS
Flammable componentFlammable component Non flammab...
PROPERTIES OF HYDROCARBONS ANDPROPERTIES OF HYDROCARBONS AND
ETHERSETHERS
PROPERTY PROPANE ISOBUTAN
E
N-
BUTANE
DIMEHTYL
E...
AdvantagesAdvantages
 InexpensiveInexpensive
 Minimal ozone depletionMinimal ozone depletion
 Negligible “greenhouse ef...
DisadvantagesDisadvantages
 FlammableFlammable
 AftertasteAftertaste
 Unknown toxicity following inhalationUnknown toxi...
HYDROCHLOROFLUOROCARBONSHYDROCHLOROFLUOROCARBONS
AND HYDROFLUOROALKANESAND HYDROFLUOROALKANES
 Several new liquefied gas ...
Conti..Conti..
 The HFC’S are extremely poor solvents and will not
dissolve a sufficient amount of the currently used
FDA...
PROPERTIES OFPROPERTIES OF
HYDROFLUOROCARBONS (HFC’S)HYDROFLUOROCARBONS (HFC’S)
PROPERTY TETRAFLUORO
ETHANE
HEPTAFLUOR
O P...
PROPERTIES OFPROPERTIES OF
HYDROCHLOROFLUOROCARBONSHYDROCHLOROFLUOROCARBONS
PROPERTY DIFLUORO
ETHANE
Molecular formula
Num...
AdvantagesAdvantages
 Low inhalation toxicityLow inhalation toxicity
 High chemical stabilityHigh chemical stability
 H...
DisadvantagesDisadvantages
 Poor solventsPoor solvents
 Minor “greenhouse effect”Minor “greenhouse effect”
 High costHi...
COMPRESSED GASESCOMPRESSED GASES
 The compressed gases such as nitrogen , nitrous
oxide and carbon dioxide have been used...
Conti..Conti..
 This system has been used for the most part to
dispense food products and for nonfoods, to
dispense the p...
PROPERTIES OF COMPRESSEDPROPERTIES OF COMPRESSED
GASESGASES
PROPERTY CARBON
DIOXIDE
NITROUS
OXIDE
NITROGEN
Molecular formu...
AdvantagesAdvantages
 Low inhalation toxicityLow inhalation toxicity
 High chemical stabilityHigh chemical stability
 H...
DisadvantagesDisadvantages
 Require use of a nonvolatile co-Require use of a nonvolatile co-
solventsolvent
 Produce cou...
CONCLUSIONCONCLUSION
 The stage has been set so that use of theThe stage has been set so that use of the
fluorocarbons is...
References
1)1) Ansel’s, “ pharmaceutical dosage formsAnsel’s, “ pharmaceutical dosage forms
and drug delivery systems”, 8...
Propellants in-pharmaceutical-aerosols
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Propellants in-pharmaceutical-aerosols

  1. 1. PROPELLANTSPROPELLANTS BYBY MADHU BURRA (M PHARM II- SEM)(M PHARM II- SEM) DEPARTMENT OF INDUSTRIAL PHARMACYDEPARTMENT OF INDUSTRIAL PHARMACY UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCESUNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES KAKATIYA UNIVERSITY,KAKATIYA UNIVERSITY, WARANGAL - 506009WARANGAL - 506009
  2. 2. CONTENTSCONTENTS  INTRODUCTIONINTRODUCTION  CLASSIFICATIONCLASSIFICATION – LIQUEFIED GASESLIQUEFIED GASES – COMPRESSED GASESCOMPRESSED GASES  NOMECLATURENOMECLATURE  DESTRUCTION OF OZONEDESTRUCTION OF OZONE  CONCLUSIONCONCLUSION  REFERENCESREFERENCES
  3. 3.  Pharmaceutical aerosols are defined as “ products containing therapeutically active ingredients dissolved, suspended, or emulsified in a propellant or a mixture of solvent and propellant, intended for topical administration, for administration into the body cavities, intended for administration orally or nasally as fine solid particles or liquid mists via the respiratory system”. INTRODUCTION
  4. 4. Components of an AerosolComponents of an Aerosol  PropellantPropellant  ContainerContainer  Valve and actuatorValve and actuator  Product concentrateProduct concentrate
  5. 5. PROPELLANTS  The propellant is generally regarded as theThe propellant is generally regarded as the heart of the aerosol package. It isheart of the aerosol package. It is responsible for development of pressureresponsible for development of pressure within the container, supplying thewithin the container, supplying the necessary force to expel the product whennecessary force to expel the product when the valve is openedthe valve is opened ..  The propellant also acts as a solvent andThe propellant also acts as a solvent and as a diluent and has much to do withas a diluent and has much to do with determing the characteristics of the productdeterming the characteristics of the product as it leaves the container.as it leaves the container.
  6. 6. CLASSIFICATIONCLASSIFICATION  Liquefied gasesLiquefied gases  Chlorofluorocarbons (CFC’s)Chlorofluorocarbons (CFC’s)  Hydro chlorofluorocarbons (HCFC’s)Hydro chlorofluorocarbons (HCFC’s)  Hydro fluorocarbons (HFC’s)Hydro fluorocarbons (HFC’s)  HydrocarbonsHydrocarbons  Compressed gasesCompressed gases  Nitrogen (NNitrogen (N22 ))  Nitrous oxide (NNitrous oxide (N22 O)O)  Carbon dioxide (COCarbon dioxide (CO22 ))
  7. 7. Liquefied - gasesLiquefied - gases Liquefied gases have been widely used as propellants for most aerosol products. Since they are gases at room temperature and atmospheric pressure. However, they can liquefied easily by lowering the temperature or by increasing the pressure. When a liquefied gas propellant is placed into a sealed container, it immediately separates into a liquid and a vapor phase. The pressure exerted against the liquid phase is sufficient to push the latter up a dip tube and against the valve. When the valve is opened, the liquid phase is emitted i.e., the pressure with in the container is decreased. Immediately a sufficient number of molecules change from liquid state to the vapor state and restore the original pressure
  8. 8. CHLOROFLUOROCARBONSCHLOROFLUOROCARBONS (CFC’S)(CFC’S)  chlorofluorocarbons (CFC’s) are inert, non toxic, non-inflammable used for oral and inhalation aerosols.  Among the Chlorofluorocarbons trichlorofluoromethane (Propellant 11), dichlorodifluoromethane (Propellant 12) and dichlorotetrafluoroethane (Propellant 114) were initially widely used in pharmaceutical aerosols.  Liquefied gases provide a nearly constant pressure during packaging operation and have large expansion ratio.
  9. 9. Conti….Conti….  Several of the fluorinated hydrocarbons have an expansion ratio of about 240 , that is 1 ml of liquefied gas will occupy a volume of app. 240 ml if allowed to vaporize.  These compounds have been implicated in causing a depletion of the ozone layer and for responsibility for the global warming effect .  In 1974, the EPA, FDA, and CPSC announced a ban on the use of CFCs, namely propellants 11, 12, and 114, in most aerosol products. Certain pharmaceutical aerosols for inhalation use (MDIs) were exempted from this ban.
  10. 10. NOMENCLATURENOMENCLATURE  To refer easily to the Fluorinated hydrocarbons a relatively simple system of nomenclature was developed by the “American Society of Refrigerating Engineers” in 1957.  According to this all propellants are designated by three digits(000).  The first digit is one less than the number of carbon atoms in the compound (C-1).  The second digit is one more than the number of hydrogen atoms in the compound (H+1).  The last digit represents the number of fluorine atoms (F).
  11. 11. Conti….Conti….  The number of chlorine atoms (for CFC’S) in the compound is found by subtracting the sum of the fluorine and the hydrogen atoms from the total number of atoms that can be added to saturate the carbon chain.  In the case of isomers , the letter a,b,c ,etc follows the number. Examples :
  12. 12. PHYSICAL PROPERTIESPHYSICAL PROPERTIES  Solubility- Non polar  Boiling point- below 240 C  Density - >1  Vapor pressure
  13. 13. VAPOR PRESSUREVAPOR PRESSURE  It is defined as the pressure exerted by a liquid in equilibrium with its vapor.  It is dependent on temperature and is independent of quantity. i.e. the vapor pressure of a pure material is the same for 1 g or 1 ton of the compound.  The vapor pressure ranges from about 13.4 psia for propellant 11 to about 85 psia for propellant 12.  Vapor pressure between these values may be obtained by blending propellant 11 with propellant 12 and propellant 12 with propellant 114.
  14. 14. Conti…Conti…  The vapor pressure of a mixture of propellants can be calculated by using Raoult’s law. Pa = [na/na+nb] PO a Pb =[nb/na+nb] P o b Where Pa and Pb are partial pressures of components a and b, na and nb are mole fraction of a and b, PO a and P o b are the vapor pressure of pure compound
  15. 15. BLENDS OFBLENDS OF CHLOROFLUOROCARBONCHLOROFLUOROCARBON PROPELLANTSPROPELLANTS PROPELLANT BLEND COMPOSITI ON VAPOR PRESSURE (psig) 700 F DENSITY (g/ml)700 F 12/1112/11 12/1112/11 12/11412/114 12/11412/114 12/11412/114 12/11412/114 50:5050:50 60:4060:40 70:3070:30 40:6040:60 45:5545:55 55:4555:45 37.437.4 44.144.1 56.156.1 39.839.8 42.842.8 48.448.4 1.4121.412 1.3961.396 1.3681.368 1.4121.412 1.4051.405 1.3901.390
  16. 16. PROPERTIES OFPROPERTIES OF CHLOROFLUOROCARBONS (CFC’S)CHLOROFLUOROCARBONS (CFC’S) PROPERTY TRICHLORO MONOFLUOR O METHANE DICHLOR O DIFLUORO METHANE DICHLORO TETRA FLUORO METHANE Molecular formula Numerical designation Molecular weight Boiling point(1atm) Vapor pressure(psia) Liquid density (gm/ml) Solubility in water (wt %) 0 F 0 C 700 F 1300 C 700 C 1300 F 770 F CCl3F 11 137.28 74.7 23.7 13.4 39.0 1.485 1.403 0.11 CCl2F2 12 120.93 -21.6 -29.8 84.9 196.0 1.325 1.191 0.028 CClF2CClF2 114 170.93 38.39 3.55 27.6 73.5 1.468 1.360 0.013
  17. 17. CHEMICAL PROPERTIESCHEMICAL PROPERTIES  HydrolysisHydrolysis  Reaction with alcohol- All propellantsReaction with alcohol- All propellants except propellants 11 are stable inexcept propellants 11 are stable in presence of alcohol.presence of alcohol.
  18. 18. AdvantagesAdvantages  Lack of inhalation toxicityLack of inhalation toxicity  Lack of flammability andLack of flammability and explosivenessexplosiveness  High chemical stability except P- 11High chemical stability except P- 11  High purityHigh purity
  19. 19. DisadvantagesDisadvantages  Destructive to atmospheric OzoneDestructive to atmospheric Ozone  Contribute to “greenhouse effect”Contribute to “greenhouse effect”  High costHigh cost
  20. 20. Destruction of OzoneDestruction of Ozone  Ozone can be destroyed by a number of free radical catalysts, the most important of which are the atomic chlorine (Cl·), hydroxyl radical (OH·), the nitric oxide radical (NO·) and bromine (Br·).  Chlorine is found in certain stable organic compounds, especially chlorofluorocarbons (CFCs), which may find their way to the stratosphere without being destroyed in the troposphere due to low reactivity. Once in the stratosphere, the Cl atoms are liberated from the parent compounds by the action of ultraviolet light, and can destroy ozone molecules through a variety of catalytic cycles.
  21. 21. Conti…Conti… CFCl3 + hν → CFCl2 + Cl Cl + O3 → ClO + O2 ClO + O → Cl + O2 In sum O3 + O → O2 + O2 =>Increase rate of recombination of oxygen, leading to an overall decrease in the amount of ozone.
  22. 22. Conti…Conti…  It is calculated that a CFC molecule takesIt is calculated that a CFC molecule takes an average of 15 years to go from thean average of 15 years to go from the ground level up to the upper atmosphere,ground level up to the upper atmosphere, and it can stay there for about a century,and it can stay there for about a century, destroying up to 100,000 ozone moleculesdestroying up to 100,000 ozone molecules during that time.during that time.
  23. 23. Ozone hole in September 2006Ozone hole in September 2006 “Largest hole in the record. ~Size of North America September 16 is "World Ozone Day"
  24. 24. Consequences of Ozone depletionConsequences of Ozone depletion  Since the ozone layer absorbs UVBSince the ozone layer absorbs UVB ultraviolet light from the Sun, ozoneultraviolet light from the Sun, ozone layer depletion is expected to increaselayer depletion is expected to increase surface UVB levels.surface UVB levels.  Possible linked to higher incidence ofPossible linked to higher incidence of skin cancer.skin cancer.  Lead to decrease of crop yield.Lead to decrease of crop yield.
  25. 25. HYDROCARBONSHYDROCARBONS  These are used in topical pharmaceutical aerosols.  They are preferred for use as a propellant over the fluorinated hydrocarbon based on their environmental acceptance and their lesser cost. However , they are flammable and explosive.  Propane, butane and isobutane are generally used as propellants.
  26. 26. Conti…Conti…  They can be blended with one another and with the fluorocarbons to obtain the desired vapor pressure and or density.  Since they are flammable, they can be blended with propellant 22,which is not flammable, to produce a non flammable product or one with less flammability than the hydrocarbon propellants.  Propellant 142 and 152 can also be used to reduce the flammability of the overall propellant blend and the product.
  27. 27. FLAMMABILITY OF PROPELLANT 22FLAMMABILITY OF PROPELLANT 22 BLENDSBLENDS Flammable componentFlammable component Non flammable belowNon flammable below this concentration (wtthis concentration (wt %)%) Propellant 142Propellant 142 Propellant 152Propellant 152 Dimethyl etherDimethyl ether HydrocarbonsHydrocarbons 7070 2424 99 5-65-6
  28. 28. PROPERTIES OF HYDROCARBONS ANDPROPERTIES OF HYDROCARBONS AND ETHERSETHERS PROPERTY PROPANE ISOBUTAN E N- BUTANE DIMEHTYL ETHER Molecular formula Molecular weight Boiling point(0 F) Vapor pressure (psig at 700 F ) Liquid density (gm/ml) Flash point(0 F) C3H8 44.1 -43.7 110.0 0.50 -156 C4H10 58.1 10.9 30.4 0.56 -117 C4H10 58.1 31.1 16.5 0.58 -101 CH3OCH3 46.1 -13 63.0 0.66 --
  29. 29. AdvantagesAdvantages  InexpensiveInexpensive  Minimal ozone depletionMinimal ozone depletion  Negligible “greenhouse effect”Negligible “greenhouse effect”  Excellent solventsExcellent solvents  Non toxic and non reactiveNon toxic and non reactive
  30. 30. DisadvantagesDisadvantages  FlammableFlammable  AftertasteAftertaste  Unknown toxicity following inhalationUnknown toxicity following inhalation  Low liquid densityLow liquid density
  31. 31. HYDROCHLOROFLUOROCARBONSHYDROCHLOROFLUOROCARBONS AND HYDROFLUOROALKANESAND HYDROFLUOROALKANES  Several new liquefied gas materials have been developed to replace the CFC’S as propellants.  Propellant 134a and propellant 227 have been developed as a substitutes for propellant 12 in MDI’s and have survived many of the short and long term toxicities.  To date , no suitable replacement has been found for propellants 11 and 114. propellant 11 is used to form a slurry with the active ingredient and dispensing agent. This is impossible to accomplish with propellants 134a and P-227
  32. 32. Conti..Conti..  The HFC’S are extremely poor solvents and will not dissolve a sufficient amount of the currently used FDA-approved surfactants (oleic acid, sorbitan, trioleate, and Soya lecithin).  HFC propellants are not compatible with some of the currently used valves.  The gaskets and sealing compounds used in MDI valves may present compatibility problems to the formulator.
  33. 33. PROPERTIES OFPROPERTIES OF HYDROFLUOROCARBONS (HFC’S)HYDROFLUOROCARBONS (HFC’S) PROPERTY TETRAFLUORO ETHANE HEPTAFLUOR O PROPANE Molecular formula Numerical designation Molecular weight Boiling point(1atm) Vapor pressure(psia) Liquid density (gm/ml) Solubility in water Flammability 0 F 0 C 700 F 1300 C 21.10 % W/W CF3CH2F 134a 102 -15.0 -26.2 71.1 198.7 1.22 0.150 Non flammable CF3CHFCF3 227 170 -3.2 -16.5 43 at (200 ) --- 1.41 0.058 Non flammable
  34. 34. PROPERTIES OFPROPERTIES OF HYDROCHLOROFLUOROCARBONSHYDROCHLOROFLUOROCARBONS PROPERTY DIFLUORO ETHANE Molecular formula Numerical designation Molecular weight Boiling point (1 atm) Vapor pressure (psia) Liquid density (g/ml) Solubility in water (wt %) 0 F 0 C 700 F 1300 F 700 F 770 F CH3CHF2 152a 66.1 -12.0 -11.0 63.0 176.3 0.91 <1.0
  35. 35. AdvantagesAdvantages  Low inhalation toxicityLow inhalation toxicity  High chemical stabilityHigh chemical stability  High purityHigh purity  Not ozone depletingNot ozone depleting
  36. 36. DisadvantagesDisadvantages  Poor solventsPoor solvents  Minor “greenhouse effect”Minor “greenhouse effect”  High costHigh cost
  37. 37. COMPRESSED GASESCOMPRESSED GASES  The compressed gases such as nitrogen , nitrous oxide and carbon dioxide have been used as aerosol propellants. Depending on the nature of the formulation and the type of compressed gas used, the product can be dispensed as a fine mist, foam, or semisolid.  However , unlike the liquefied gases, the compressed gases possess little expansion ratio (3- 10 times) and will produce a fairly wet spray and foams that are not as stable as liquefied gas foams.
  38. 38. Conti..Conti..  This system has been used for the most part to dispense food products and for nonfoods, to dispense the product in its original form as a semisolid.  Compressed gases have been used in products such as dental creams, hair preparations , ointments, and aqueous anti septic and germicidal aerosols and are extremely useful in contact lens cleaner saline solution and barrier systems.
  39. 39. PROPERTIES OF COMPRESSEDPROPERTIES OF COMPRESSED GASESGASES PROPERTY CARBON DIOXIDE NITROUS OXIDE NITROGEN Molecular formula Molecular weight Boiling point(0 F) Vapor pressure (psia, 700 F) Solubility in water, 770 F Density (gas) gm/ml CO2 44 -109 852 0.7 1.53 N2O 44 -127 735 0.5 1.53 N2 28 -320 492 0.014 0.96699
  40. 40. AdvantagesAdvantages  Low inhalation toxicityLow inhalation toxicity  High chemical stabilityHigh chemical stability  High purityHigh purity  InexpensiveInexpensive  No environmental problemsNo environmental problems
  41. 41. DisadvantagesDisadvantages  Require use of a nonvolatile co-Require use of a nonvolatile co- solventsolvent  Produce course droplet spraysProduce course droplet sprays  Pressure falls during usePressure falls during use
  42. 42. CONCLUSIONCONCLUSION  The stage has been set so that use of theThe stage has been set so that use of the fluorocarbons is severely limited and their usefluorocarbons is severely limited and their use will become increasingly prohibitive.will become increasingly prohibitive.  Hydrofluoroalkanes provide a safe alternativeHydrofluoroalkanes provide a safe alternative to CFC’S as propellants in aerosols, but theirto CFC’S as propellants in aerosols, but their physicochemical properties have requiredphysicochemical properties have required extensive redevelopment of the entire product.extensive redevelopment of the entire product.  Hydrofluoroalkanes are not environmentallyHydrofluoroalkanes are not environmentally neutral and contribute to hydrocarbonneutral and contribute to hydrocarbon emissions, global warming and acid rain.emissions, global warming and acid rain.
  43. 43. References 1)1) Ansel’s, “ pharmaceutical dosage formsAnsel’s, “ pharmaceutical dosage forms and drug delivery systems”, 8and drug delivery systems”, 8thth editionedition 2)2) Remington , " The science and practiceRemington , " The science and practice of pharmacy “ , 21of pharmacy “ , 21stst editionedition 3)3) Leon. Lachman, “The Theory andLeon. Lachman, “The Theory and Practice of Industrial Pharmacy”, 3Practice of Industrial Pharmacy”, 3rdrd editionedition 4)4) Gilbert S.Banker, “ pharmaceuticalGilbert S.Banker, “ pharmaceutical dosage forms” disperse systems;dosage forms” disperse systems; volume 2; 2volume 2; 2ndnd editionedition 5)5) Bentley, “ Text book of pharmaceutics”,Bentley, “ Text book of pharmaceutics”, 88thth editionedition 6)6) ““Indian Pharmacopoeia”, 2007, Vol-2Indian Pharmacopoeia”, 2007, Vol-2 7) www.sciencedirectory.com 8) www.wikipedia.com

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